Evaluation of the mTOR Inhibitor Rapamycin in Dogs with Osteosarcoma

Purpose

To define and compare three schedules for chronic delivery of rapamycin using a variety of biological endpoints. Dogs will be monitored to determine if objective antitumor activity is associated with rapamycin administration in dogs with established lung metastasis.

Background

Despite amputation of the affected limb and the administration of chemotherapy, nearly all dogs with osteosarcoma will eventually develop spread of disease to other parts of the body. In most cases, the osteosarcoma spreads to the lungs. Unfortunately, once the osteosarcoma has spread to the lungs it is extremely resistant to treatment with chemotherapy, and most dogs don't live beyond 2-3 months following diagnosis of the spread. The purpose of this study is to determine the best treatment schedule for a new type of treatment, rapamycin, on for osteosarcoma that has spread to the lungs. This drug works by inhibiting the mTOR pathway, which is believed to be the “nutrient sensor” of the cell. Proteins important in cancer progression and resistance to cancer therapy are affected by this pathway. Side effects from rapamycin were minimal in a previous clinical trial where this drug was given daily by intramuscular injection for one week.

Eligibility Criteria

To be eligible for this trial, dogs must:

  • have radiographically measurable osteosarcoma pulmonary metastases (may be presumed based on clinical history)
  • have a pulmonary metastatic burden < 15 metastatic lesions; no lesion greater than 5 cm diameter
  • have a favorable performance status
  • have informed owner consent for trial, including consent to autopsy if they die while on study

Baseline Evaluation for Eligibility

All dogs require the following baseline evaluations before eligibility can be assessed. These tests must be performed within two weeks of study initiation:

  • physical examination and weight
  • CBC, serum biochemistry, urinalysis
  • thoracic radiographs (3 views)
  • measurement of tumor burden (via thoracic radiographs)

Exclusion Criteria

  • dogs < 10 kg in size
  • dogs without measurable disease concurrent chemotherapy (including corticosteroids) or radiation therapy
  • Dogs must be off of all such therapy for 2 weeks prior to study enrollment
  • NSAID use within 72 hours of study initiation
  • dogs with a history of Inflammatory Bowel Disease (IBD) or chronic gastroenteritis
  • significant co-morbid illness, which includes renal or hepatic failure, history of congestive heart failure or clinical coagulopathy
  • any grade 3 hematologic or biochemical toxicity

Study Design

Dogs eligible for the study will have baseline thoracic radiographs performed to measure the tumors and blood samples collected. Dogs will then be sequentially assigned to each of the three treatment schedules (5 days on/2 days off, every other day, 1 week on/1 week off). Drug (rapamycin) will be administered intramuscularly by the owner according to the treatment schedule. Patients will be reassessed at the Ohio State University Veterinary Medical Center (OSU-VMC) on days 6, 13, and 30, then every 30 days thereafter while on study. History, physical examination, and blood sampling will be done at each of these visits. Thoracic radiographs will be repeated to assess tumor response at day 30 and every 30 days thereafter while on study. After day 30, as long as tumors are stable or smaller in size, the dog can continue to receive drug with re-check visits at the OSU-VMC every 30 days. Dogs with tumors that have increased in size (progressive disease) may be given an increased dose (dose escalated) for the next 30 days of treatment. Dog owners will be instructed on proper dosing and handling of rapamycin and they will be given an Owner Assessment Form to record their impressions of their dog's clinical status during the study period.

Client Compensation

All costs related to the study (bloodwork, radiographs, office visits, etc.) once the patient is enrolled in the study are covered by the study. If the dog should become sick from the drug (vomiting, diarrhea), treatment for this will also be covered by the study.

Contact Information

For more information on this study, please contact:

  • Dr. William C. Kisseberth phone: 614-247-7201
  • Dr. Cheryl A. London (clinicaltrials [at] cvm [dot] osu [dot] edu)
  • Dr. C. Guillermo Couto phone: 614-292-3551